title: Blocking transforming growth factor-β signaling pathway augments antitumor effect of adoptive NK-92 cell therapy.
abstract: Natural killer (NK) cells hold great potential for improving the immunotherapy of cancer. However, existing data indicate that tumor cells can effectively escape NK cell-mediated apoptosis through immunosuppressive effect in the tumor microenvironment. Transforming growth factor-β (TGF-β) is a potent immunosuppressant. The present study was intended to develop a treatment strategy through adoptive transfer of TGF-β insensitive NK-92 cells. To block TGF-β signaling pathway, NK-92 cells were genetically modified with dominant negative TGF-β type II receptor (DNTβRII) by optimizing electroporation using the Amaxa Nucleofector system. These genetically modified NK-92 cells were insensitive to TGF-β and able to resist the suppressive effect of TGF-β on Calu-6 lung cancer cells in vitro. To determine the antitumor activity in vivo, recipient mice were challenged with a single subcutaneous injection of Calu-6 cells. Adoptive transfer of TGF-β insensitive NK-92 cells decreased tumor proliferation, reduced lung metastasis, produced more IFN-γ, and increased the survival rate of nude mice bearing established Calu-6 cells. Hence, we have demonstrated that blocking transforming growth factor-β signaling pathway in NK cells provides a novel therapeutic strategy and warrants further investigation.
authors.affiliation: Department of Oncology, General Hospital of Chinese PLA, Beijing, People's Republic of China.
authors.forename: Bo
authors.initials: B
authors.lastname: Yang
authors.forename: Hui
authors.initials: H
authors.lastname: Liu
authors.forename: Weiwei
authors.initials: W
authors.lastname: Shi
authors.forename: Zhikuan
authors.initials: Z
authors.lastname: Wang
authors.forename: Shenjie
authors.initials: S
authors.lastname: Sun
authors.forename: Guoqing
authors.initials: G
authors.lastname: Zhang
authors.forename: Yi
authors.initials: Y
authors.lastname: Hu
authors.forename: Tianyi
authors.initials: T
authors.lastname: Liu
authors.forename: Shunchang
authors.initials: S
authors.lastname: Jiao
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D003602:Cytotoxicity, Immunologic; D006801:Humans; D007165:Immunosuppression Therapy; D016219:Immunotherapy, Adoptive / Q000379:methods*; D007694:Killer Cells, Natural / Q000276:immunology* / Q000637:transplantation; D008175:Lung Neoplasms / Q000276:immunology / Q000628:therapy*; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D009374:Neoplasms, Experimental / Q000276:immunology / Q000628:therapy*; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors*; D000077294:Receptor, Transforming Growth Factor-beta Type II; D018125:Receptors, Transforming Growth Factor beta / Q000037:antagonists & inhibitors*; D015398:Signal Transduction; D051899:Smad2 Protein / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000037:antagonists & inhibitors*; D019076:Transgenes / Q000235:genetics; D059016:Tumor Microenvironment; D023041:Xenograft Model Antitumor Assays
chemical_list: D018125:Receptors, Transforming Growth Factor beta; D051899:Smad2 Protein; D016212:Transforming Growth Factor beta; D017346:Protein Serine-Threonine Kinases; D000077294:Receptor, Transforming Growth Factor-beta Type II
keywords: Adoptive cell therapy; Cancer; Natural killer-92 cell; Nucleofection; Transforming growth factor-β